Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that can induce endochondral bone formation in adult animals. This superfamily includes a large group of structurally related signaling proteins that are secreted as dimers and then cleaved to result in biologically active carboxy terminal domains of the proteins. These bioactive proteins are characterized by 7 highly conserved cysteine residues. Interestingly, these proteins have different roles at various stages of embryogenesis and in adult animals. Recombinant BMPs are now available and have been shown to induce endochondral bone formation when assayed in vivo.
Indeed, the initial discovery of the BMPs was facilitated by such in vivo assays for cartilage and bone development. These assays were based on the observation that bone development could be initiated by subcutaneous or intramuscular implantation of compositions comprising an extract of demineralized bone and residual bone powder. The novel proteins identified in the extracts were termed “bone morphogenetic proteins.” These proteins were subsequently classified as members of the TGF-β superfamily by virtue of amino acid sequence relatedness. Screening of genomic and cDNA libraries led to the isolation of polynucleotides encoding BMP-2, -3, -4, -5, -6 and -7.
One deficiency of the bone induction assay regards its inability to distinguish the physiological roles of different BMP family members. The cartilage and bone inducing activity of the BMPs is remarkable because the normal stages of endochondral bone formation that occur during ontogeny are recapitulated in the adult animal. These stages include mesenchymal condensation, cartilage and bone and bone marrow formation and eventual mineralization to produce mature bone.
Several observations suggest that BMPs have wide-ranging extraskeletal roles in development. First, localization studies in both human and mouse tissues have demonstrated high levels of mRNA expression and protein synthesis for various BMPs in kidney (BMPs -3, -4, -7), lung (BMPs -3, -4, -5, -6), small intestine (BMPs -3, -4, -7), heart (BMPs -2, -4, -6, limb bud (BMPs -2, -4, -5, -7) and teeth (BMPs -3, -4, -7). Second, several members of the family, including BMP-4 and -7, are key molecules in epithelial-mesenchymal interactions, for instance during odontogenesis. Third, BMP-2 and BMP-4 are involved in the signaling pathway that controls patterning in the developing chick limb and BMP-4 is a ventralizing factor in early Xenopus development. Fourth, Drosophila homologs of the BMPs, the decapentaplegic (dpp) and 60 A gene products, have the capacity to induce bone in mammals whereas human BMP-4 confers normal embryonic dorso-ventral patterning in Drosophila transformants defective in dpp expression. Thus, the BMPs are now appreciated as pleiotropic cytokines.
Interestingly, none of the known BMPs are strongly expressed in the chondroblasts and chondrocytes of the cartilage core of developing long bones. The hypertrophic chondrocytes, where both Vgr-1 (BMP-6, (Lyons et al., Development 109:833 (1990)) and OP-1 (BMP-7)(Vukicevic et al., Biochem. Biophys. Res. Commun. 198:693 (1994)) have been found are exceptions in this regard.